Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-07-05 Epub Date: 2024-06-04 DOI:10.1161/CIRCRESAHA.124.324327
Alastair J S Webb, Jacqueline S Birks, Karolina A Feakins, Amy Lawson, Jesse Dawson, Alexander M K Rothman, David J Werring, Osian Llwyd, Catriona R Stewart, James Thomas
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Abstract

Background: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown.

Methods: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q.

Results: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013).

Conclusions: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease.

Registration: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

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西地那非对小血管疾病的脑血管效应:OxHARP 试验
背景:脑小血管疾病导致的血管性认知障碍与脑搏动性、白质灌注不足和脑血管反应性(CVR)降低有关,西洛他唑等内皮靶向药物可能会改善这些症状。磷酸二酯酶-5抑制剂西地那非是否能改善脑血管功能障碍尚不清楚:OxHARP试验(牛津血流动力学适应以降低脉动性)是一项双盲、随机、安慰剂对照、三向交叉试验,研究对象是非栓塞性脑血管事件后出现轻度-中度白质增厚(WMH)的患者,白质增厚是脑小血管疾病的最常见表现。主要研究结果评估了西地那非 50 毫克、每天三次(混合效应线性模型)与安慰剂相比,西地那非 50 毫克、每天三次(混合效应线性模型)对大脑中动脉搏动性(由收缩峰值和舒张末期速度(经颅超声)得出)的疗效优于西洛他唑 100 毫克、每天两次(混合效应线性模型),而西洛他唑 100 毫克、每天两次(混合效应线性模型)对大脑中动脉搏动性的疗效不劣于西洛他唑 100 毫克、每天两次。次要终点包括:经颅超声吸入空气、4%和6%二氧化碳时的脑血管反应性(经颅超声-CVR);WMH(CVR-WMH)和正常外观白质(CVR-正常外观白质)内的血氧水平依赖性磁共振成像;动脉自旋标记(磁共振成像假连续动脉自旋标记)的脑灌注;以及脑血管传导阻力。通过 Cochran Q 对不良反应进行比较:在 65/75 (87%) 例具有有效主要结果数据的患者(中位年龄 70 岁;79% 男性)中,西地那非与安慰剂相比(0.02,-0.01 至 0.05;P=0.18)或与西洛他唑相比(-0.01,-0.04 至 0.02;P=0.36),脑搏动性保持不变,尽管血流量有所增加(∆ 收缩峰值速度,6.3 cm/s,3.5-9.07;PP=0.004)。与安慰剂相比,西地那非改善了以下次要结果:CVR-经颅超声(0.83 厘米/秒/毫米汞柱,0.23-1.42;P=0.007)、CVR-WMH(0.07,0-0.14;P=0.043)、CVR-正常外观白质(0.06,0.00-0.12;P=0.048)、灌注(WMH:1.82毫升/100克每分钟,0.5-3.15;P=0.008;正常外观白质,2.12,0.66-3.6;P=0.006)和脑血管阻力(西地那非-安慰剂:0.08,0.05-0.10;P=4.9×10-8;西洛他唑-安慰剂:0.06,0.03-0.09;P=5.1×10-5)。两种药物都会增加头痛(P=1.1×10-4),而西洛他唑会增加中度-重度腹泻(P=0.013):结论:西地那非没有降低搏动性,但增加了脑血管反应性和灌注。西地那非值得进一步研究,以确定它是否能预防小血管疾病的临床后遗症:URL:https://www.clinicaltrials.gov;唯一标识符:NCT03855332。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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